PROJECT SUMMARY/ABSTRACT Many rural communities are medically underserved and experience persistently elevated rates of colorectal cancer (CRC) incidence and mortality relative to declining national rates. Routine screening reduces population CRC mortality, yet its impact is reduced because many adults who have an abnormal screening result with fecal testing do not receive diagnostic follow-up with colonoscopy. Rural residents and healthcare providers face unique barriers to screening follow-up including fewer providers who offer colonoscopy and longer travel distances to obtain healthcare. Rural Southern Illinois is a region with high poverty, slow economic growth, isolated households, widely dispersed medical care, and high CRC mortality. To reduce disparities in CRC mortality in rural areas where fecal immunochemical testing (FIT) is a common first-line screening strategy, we must identify effective, sustainable, and disseminable strategies to improve follow-up of positive screening tests. Researchers at Washington University School of Medicine have collaborated with Southern Illinois Healthcare, a rural not-for-profit health system, since 2015 to identify cancer prevention and control priorities and reduce disparities. From 2017 to 2018, we conducted a formal pre-implementation assessment of CRC screening and follow-up processes to identify feasible and promising evidence-based interventions and strategies for improvement. Based on our substantial and specific preliminary data, we propose the following Aims: Aim 1. Implement a multilevel intervention of follow-up of abnormal colon cancer screening tests in primary care clinics across rural Southern Illinois. Using a stepped wedge trial design and cluster randomization, we will implement the multi-level intervention in 18 clinics. We will intervene at three levels (patients, providers/clinical teams, clinics) and evaluate implementation outcomes per Proctor's evaluation model using interviews, surveys, and field notes. Aim 2. Evaluate the impact of the multilevel intervention on follow-up of abnormal screening test results in rural primary care settings in Southern Illinois. Our stepped-wedge design will allow us to test the impact of the multi-level intervention on rates of screening follow-up. We measure outcomes at three levels. Patient: After positive FIT, receipt of referral and completion of colonoscopy. Primary Care Provider: Receipt of positive FIT results and referral for follow-up. Clinic-level: Patients with positive FIT complete colonoscopy. We will assess change in CRC screening rates and investigate interactions between and across levels. Data for primary outcomes will come from the healthcare system's ongoing patient registry that draws from electronic medical records and lab records. The co- construction of this proposal between university researchers and health system stakeholders enhances the potential for significant and sustainable change for effective and efficient screening and early detection. There is a critical need for real-world strategies that can function within rural community health systems to improve health and reduce disparities.